1. Renal insufficiency and TKI ? Myth or Reality
Vincent LAUNAY-VACHER
Service ICAR, CHU Pitié-Salpêtrière, Paris
Friday September 2, 2016
Paris

2. COI Vincent Launay-Vacher 3 years
Indirect links (Research grants, eJournals, Educational grants, …) Amgen, Bayer, Boehringer-Ingelheim, Daiichi-Sankyo, Gilead, Hospira, Ipsen, Leo Pharma, Pierre Fabre, Roche, Teva, Vifor Pharma
Direct links (Consulting, Talks, …) Amgen, Leo Pharma, Pierre Fabre Oncology, Roche, Sanofi, Takeda, Teva
Service ICAR
SiteGPR
Cancer & the Kidney International Network

3. Renal insufficiency is highly frequent in cancer
France1,2 : IRMA studies (IRMA-1 and IRMA-2)
4’684 et 4’945 patients (all types of solid tumors)
DFG<60 : 12.0% et 11.8% (MDRD)
Belgium3 : B-IRMA study
1’218 patients (all types of solid tumors)
DFG<60 : 16.1% (MDRD)
United-States4 :
1’114 patients (kidney cancer)
DFG<60 : 22,0% (MDRD)
Japan5 :
231 patients (all types of solid tumors)
DFG<60 : 25.0% (MDRD)
Austria6 :
1’100 patients (all types of solid tumors)
DFG<60 : 14.7% (MDRD) et 16.1% (CKD-EPI)
Prevalence varies
from 12 to 25%
1Launay-Vacher V et al. Cancer 2007; 2Launay-Vacher V et al. Semin Nephrol 2010;
3Janus N et al. Br J Cancer 2010; 4Canter D et al. Urology. 2011;
5Nakamura Y et al. Nihon Jinzo Gakkai Shi. 2011; 6Königsbrügge O et al. Thromb Res 2014

4. Renal insufficiency is highly frequent in cancer
Whatever the type of tumor, only a MINORITY of patients present with NORMAL renal function
1Launay-Vacher V et al. Breast Cancer Res Treat 2010; 2Launay-Vacher V et al. Lung 2009;
3Launay-Vacher V et al. Clinical Genit Cancer 2009; 4Personal data IRMA-1

5. Renal insufficiency in kidney cancer
23%
21%
22%
12,5%
22%
22%
Canter D et al. Urology. 2011

6. Renal insufficiency impacts survival
France1 :
DFG<60 => Decreased Overall Survival
HR 1.27 (p=0.0002)
Japan2 :
DFG<60 = independent risk factor for increased 1-year mortality
Korea3 :
30<DFG<60 => HR 1.12 (p=0.04) for increased cancer-related mortality
DFG<30 => HR 1.75 (p<0.001) for increased cancer-related mortality
Australia4 :
DFG<60 => increased cancer-related mortality
HR 1.27
Each decrease in GFR of 10 ml/min/1.73m2 = 18% increase in cancer-related mortality (p<0.001)
1Launay-Vacher V et al. Semin Nephrol 2010; 2Nakamura Y et al. Nihon Jinzo Gakkai Shi. 2011;
3Na SY, et al. Am J Nephrol. 2011; 4Iff S, et al. Am J Kidney Dis 2014

7. Links Renal insufficiency  Survival
The physio-pathological hypothesis
Increased cardiovascular morbi-mortality in patients with cancer and renal insufficiency
The pharmacological hypotheses

8. Renal insufficiency patients are at risk for renal TOXICTY
Renal insufficiency => Risk factor for Acute Kidney Injury (AKI)
More frequent
More severe

9. Cancer drugs with a renal risk
Immune checkpoint inhibitors
Toxicity
Incidence
Ipilimumab
Nivolumab
Pembrolizumab
Estimated cost
Renal failure
13,9%
9,9%
$8854
Colitis
10,2%
10,9%
9,7%
$8563
Hypopituitarism
20,4%
4,0%
7,6%
$4979
Nephritis
1,6%
2,0%
0,0%
$4218
Peripheral neuropathy
12,8%
33,7%
16,7%
$3960
Oliguria/Anuria
1,0%
$3807
Pancreatitis
1,8%
2,8%
$3590
Dyspnea
8,4%
31,7%
8,3%
$3345
Fever
17,8%
22,8%
20,8%
$3304
Pneumonitis
0,5%
0,7%
$2580
Ventricular arythmia
18,8%
$2246
Seizures
5,6%
$2167
Fatigue
72,0%
87,1%
91,0%
$2069
Myalgia/Pain
8,1%
7,9%
$1947
Nausea/Vomiting
47,9%
59,4%
54,9%
$1442
Neutropenia
21,5%
16,8%
26,4%
$859
Thrombocytopenia
12,0%
14,9%
10,4%
$854
Anemia
42,9%
34,0%
$851
Diarrhea
15,8%
40,3%
$775
Hypo/Hyperthyroidism
33,5%
39,6%
38,2%
$583
Hepatitis
3,5%
$529
Renal toxicities: % incidence
- Highly costly
Mason NT. et al.- ASCO® Abs 6627

10. Acute Kidney Injury impacts survival
In cancer patients (MD Anderson study)
An increase in SCr of 10% as compared to baseline is associated with increased in-hospital mortality
An increase in SCr of 25% during the first 72 hours in ICU is associated with a doubling in mortality: versus 30.1%, p<0.001
NCI-CTCAE v4
Increase of 50 to 100%
SamuelsJ et al. Support Care Cancer 2011

11. Links Renal insufficiency  Survival
The physio-pathological hypothesis
Increased cardiovascular morbi-mortality in patients with cancer and renal insufficiency
The pharmacological hypotheses
Patients at risk for AKI => increased mortality

12. Non-optimal use of cancer drugs
If RI has not been identified or
If RI has been identified
but no dosage adjustment
OVERDOSAGE
Dose-related toxicities
Consequences these toxicities:
- Delayed courses
- Change in treatment
- Switch to palliative care (Elderly +++)

13. Non-optimal use of cancer drugs
If RI has not been identified or
If RI has been identified
but no dosage adjustment
If RI has been identified
But dosage adjustment:
Too much reduced
Empirical adjustment
OVERDOSAGE
Toxicity
UNDER -DOSAGE
Lack of efficacy
Crucial to prescribe the right dosage,
adjusted to patient’s renal function

14. Non-optimal use of cancer drugs
This is not only theory: This is real-life
Monocentric prospective observational study
Metastatic colorectal cancer, all patients treated the same, « normal » SCr
Capecitabine + Oxaliplatin (4 courses)
Capecitabine: 1000 mg/m2, twice daily, D1-14, Q3W
Oxaliplatin: 130 mg/m2, D1, Q3W
Chen J, et al. Support Care Cancer 2015

15. Non-optimal use of cancer drugs
This is not only theory: This is real-life
Increased toxicity
Chen J, et al. Support Care Cancer 2015

16. Non-optimal use of cancer drugs
This is not only theory: This is real-life
More treatment interruptions or modifications
Reduced survival
(Time to progression) =>
Adjusted HR TTP
1.57 [1.09–2.25]
P=0.015
Chen J, et al. Support Care Cancer 2015

17. Links Renal insufficiency  Survival
The physio-pathological hypothesis
Increased cardiovascular morbi-mortality in patients with cancer and renal insufficiency
The pharmacological hypotheses
Patients at risk for AKI => increased mortality
Patients at risk for a non-optimal use of cancer drugs:
When dosage is not adjusted to renal function, survival is reduced (time to progression, metastatic colorectal cancer)

18. Non-optimal use of cancer drugs
This is not only theory: This is real-life
Prospective interventional study
Adjuvant breast cancer (Age ≥ 65 years)
Patients treated with:
CMF (Cyclophosphamide, Methotrexate, Fluorouracile)
AC (Doxorubicine, Cyclophosphamide)
Capecitabine
Dosage adjusted to renal function
Lichtman SM, et al. J Clin Oncol 2016

19. Non-optimal use of cancer drugs
This is not only theory: This is real-life
Endpoints :
Overall survival (OS)
Relapse-free survival (RFS)
Analyses of the effect of renal function on survival:
GFR as a discontinuous variable: « early » vs. « late » => Survival curves
GFR as a continuous variable => Hazard Ratios
Stade
DFG
N (%)
CMF AC
Capé 1
≥90
3 (2)
5 (3)
5 (2) 2
60-89
34 (25)
61 (34)
71 (24) 3
30-59
95 (70)
112 (62)
224 (74) 4
15-29
4 (2)
2 (1) 5
<15
0 (0)
CMF : Cyclophosphamide, Méthotrexate, Fluorouracile ; AC : Doxorubicine, Cyclophosphamide ; Capé : Capécitabine
Only 7% of patients with normal GFR
Lichtman SM, et al. J Clin Oncol 2016

20. Non-optimal use of cancer drugs
This is not only theory: This is real-life
RELAPSE-FREE SURVIVAL
CMF AC
Capé
Endpoint
HR [95% CI] P
Relapse-free survival
CMF
1,06 [0,86-1,33] NS AC
1,08 [0,90-1,28]
Capecitabine
0,93 [0,80-1,08]
CMF : Cyclophosphamide, Méthotrexate, Fluorouracile ; AC : Doxorubicine, Cyclophosphamide
Lichtman SM, et al. J Clin Oncol 2016

21. Non-optimal use of cancer drugs
This is not only theory: This is real-life
OVERALL SURVIVAL
CMF AC
Capé
Endpoint
HR [95% CI] P
Overall survival
CMF
1,10 [0,87-1,41] NS AC
1,05 [0,87-1,27]
Capecitabine
0,92 [0,78-1,09]
CMF : Cyclophosphamide, Méthotrexate, Fluorouracile ; AC : Doxorubicine, Cyclophosphamide
Lichtman SM, et al. J Clin Oncol 2016

22. Links Renal insufficiency  Survival
The physio-pathological hypothesis
Increased cardiovascular morbi-mortality in patients with cancer and renal insufficiency
The pharmacological hypotheses
Patients at risk for AKI => increased mortality
Patients at risk for a non-optimal use of cancer drugs:
When dosage is not adjusted to renal function, survival is reduced (time to progression, metastatic colorectal cancer)
When dosage is adjusted to renal function, survival in RI patients is similar to that of normal renal function patients (OS and RFS, adjuvant breast cancer in the elderly)

23. Renal insufficiency and TKIs
Hepatic metabolism => No dosage adjustment required in patients with RI
Hepatic metabolism may be reduced in CKD
Uremic toxins may alter:
The hepatic uptake of drugs
CYP activity
MYTH

24. Renal insufficiency and TKIs
Hepatic metabolism => No dosage adjustment required in patients with RI
Hepatic metabolism can be reduced in CKD
Do not forget the metabolites !
MYTH
Van Erp NP, et al. Cancer Treatment Reviews 2009

25. Renal insufficiency and TKIs
THE REALITY
Example of Vandetanib:
Oral tyrosine kinase inhibitor (VEGFR-2, EGFR, and RET)
Renal excretion accounts for less than 25% of the administered drug
Hepatic metabolism / biliary excretion are the main routes of elimination
However, vandetanib PKs are altered in renal impairment:
Clearance reduced by 30% and AUC increased by 40%1
AUC increased from 1.5 to 2-fold in mild to severe renal impairment2
Dosage adjustment is required
Weil A, et al. Clin Pharmacokinet 2010 ; Caprelsa®. Summary of product characteristics. EMA, 2012

26. Vandetanib PKs in liver and renal impairment
x 1,08
x 0,93
x 1,41
x 0,71
Weil A, et al. Clin Pharmacokinet 2010 ; Caprelsa®. Summary of product characteristics. EMA, 2012

27. Renal insufficiency and TKIs
THE REALITY
Example of Vandetanib:
Oral tyrosine kinase inhibitor (VEGFR-2, EGFR, and RET)
Renal excretion accounts for less than 25% of the administered drug
Hepatic metabolism / biliary excretion are the main routes of elimination
Vandetanib PKs are altered in renal impairment:
Clearance reduced by 30% and AUC increased by 40%1
AUC increased from 1.5 to 2-fold in mild to severe renal impairment2
Dosage adjustment is required
Weil A, et al. Clin Pharmacokinet 2010 ; Caprelsa®. Summary of product characteristics. EMA, 2012

28. Renal insufficiency and TKIs
THE REALITY
Example of Vandetanib:
PKs are altered in RI
Dosage adjustment is required
Example of Sunitinib:
Weil A, et al. Clin Pharmacokinet 2010 ; Caprelsa®. Summary of product characteristics. EMA, 2012

29. Decreased exposition to sunitinib AND its metabolite in RI
AUC(0-48)
Normal
Severe RI
ESRD
Sunitinib
1892
1781
998
SU12662
719
580
504
Sum
2611
2361
1502
Difference vs. Normal
-9,6%
-42,5%
Sunitinib
Decreased exposition to sunitinib AND its metabolite in RI
Authors conclude that the safety is OK
What about the efficacy ?
Metabolite
Khosravan R et al. J Clin Pharmacol 2009

30. Renal insufficiency and TKIs
THE REALITY
Example of Vandetanib:
PKs are altered in RI
Dosage adjustment is required
Example of Sunitinib:
PKs are altered
Dosage adjustment ?
Weil A, et al. Clin Pharmacokinet 2010 ; Caprelsa®. Summary of product characteristics. EMA, 2012

31. Renal insufficiency and TKIs
THE REALITY
TKI
Pharmacokinetic modifications in CKD ?
Risk
Dosage adjustment in CKD
Axitinib
No data ?
Erlotinib No -
Not required
Lapatinib
Sorafenib
 Toxicity has been reported
Sunitinib
YES: exposition 
Under-Dosage
Theoretically yes, but how ?
Vandetanib
YES: exposition 
Over-Dosage
200 mg in moderate RI Not recommended in severe RI
SiteGPR (

32. CONCLUSIONS Renal insufficiency is highly frequent in cancer patients
Renal Insufficiency is associated with increased cancer- related mortality
The main cause is a non-optimal use of cancer drugs (dosage adjustment)
TKI can require dose adjustment, even if the liver is the main route of elimination
Data are lacking on how to adjust TKI dosage in Renal Insufficiency

33. Education and research on cancer and renal insufficiency
Dosage adjustments
Education and research on cancer and renal insufficiency

34. Thank you…
…for your attention !